Purpose

Functional magnetic resonance imaging (fMRI) can indirectly measure brain activity because its blood oxygen level-dependent (BOLD) signal largely depends on neurovascular coupling, which refers to the processes by which neural activity influences the haemodynamic properties of the surrounding vasculature. Nevertheless, the biochemical underpinnings of such BOLD changes cannot be elucidated using fMRI alone. A promising technique for bridging the gap, by virtue of measuring in-vivo brain metabolite concentrations, is proton magnetic resonance spectroscopy (¹H-MRS). One of the important metabolites which ¹H-MRS can detect is Glx [summation of glutamate (Glu) and glutamine (Gln)], where Glu is one of the mediators of neurovascular coupling and its concentration would influence the BOLD signal changes.¹ In this study, we aim to elucidate the complex relationship between attention control (numerical Stroop) and its associated neurochemical changes by combining the biochemical information obtained from task-based fMRI and ¹H-MRS.

Methods

A total of 90 healthy subjects will be recruited for the entire research project, approximately 15 subjects in each decade between 20 and 90. Potential subjects will be interviewed to gather socio-demographic data and undergo neuropsychological assessments. Only subjects with scores ≥28 in MMSE and ≥26 in MoCA will be included in the study. Written informed consent will also be obtained. 37 subjects were currently scanned. All experiments were performed with 3.0T Philips scanner using a standard head coil. Structural images were acquired with 3D fast field echo sequence (3D-T1-FFE sagittal). For the ¹H-MRS part, PRESS (TR/TE = 2000/39 ms) single voxels of 2 x 2 x 2 cm³ were placed in the ACC (Figure 1a). Choline (Cho), creatine (Cr), N-acetyl aspartate (NAA), myo-inositol (mI), and summation of glutamate and glutamine complex (Glx), were measured and quantified using internal water as reference by QUEST in jMRUI (4.0)(Figure 1b,c). Cerebrospinal fluid (CSF) normalization, water content correction for grey matter, white matter and CSF, and correction factors for T1 and T2 relaxation were also implemented. The task-based functional images were collected by using a gradient-echo-planar sequence sensitive to blood-oxygen-level-dependent (BOLD) contrast in a numerical Stroop task (Figure 2). Data analysis was performed using Statistical Parametric Mapping (SPM12). The preprocessing process includes motion correction, normalization, and smooth with a Gaussian kernel of 8 mm FWHM (full width at half maximum). In the first level analysis, the coefficients for each contrast were estimated separately in the fixed event-related effect model. In the second level analysis, the consistency of these coefficients was estimated using the linear regression module with absolute concentrations of metabolites from 1H-MRS as the covariates.

Results

The demographic information and mean absolute concentrations of metabolites from ¹H-MRS were shown in Table 1. The anterior cingulate cortex (ACC), right inferior frontal gyrus, bilateral insula and medial frontal gyrus were positively correlated with the absolute concentration of Glx ([Glx]_abs) (Figure 3). Other metabolites showed no correlation with ACC activation.

Discussion

Our novel finding of [Glx]_abs significantly positively correlated with the activated region over the ACC provides a neurochemical basis of neural activations observed in the attention control task, i.e. numerical Stroop. As mentioned, [Glx]_abs consists of both Glu and Gln, where Glu is the primary excitatory neurotransmitter, and together with its precursor, Gln, they form the Glu-Gln cycle. In other words, [Glx]_abs can be deemed as a central measure of glutamatergic neurotransmission. The ACC is involved in attention control and its rich glutamatergic innervation has been reported in prior studies.^2,3 As such, an elevation in this glutamatergic activity may then lead to the observed task-induced activation in the ACC.

Conclusion

This is the first study which provides a neurochemical explanation of the BOLD change during an attention control task (numerical Stroop), identifying Glx as the excitatory neurotransmitter mediating the neurovascular coupling.

Acknowledgements

No acknowledgement found.